Schizophrenia is associated with cognitive deficits that reflect impaired cortical information processing. Mismatch negativity (MMN) indexes pre-attentive information processing dysfunction at the ...level of primary auditory cortex. This study investigates mechanisms underlying MMN impairments in schizophrenia using event-related potential, event-related spectral decomposition (ERSP) and resting state functional connectivity (rsfcMRI) approaches. For this study, MMN data to frequency, intensity and duration-deviants were analyzed from 69 schizophrenia patients and 38 healthy controls. rsfcMRI was obtained from a subsample of 38 patients and 23 controls. As expected, schizophrenia patients showed highly significant, large effect size (P=0.0004, d=1.0) deficits in MMN generation across deviant types. In ERSP analyses, responses to deviants occurred primarily the theta (4-7 Hz) frequency range consistent with distributed corticocortical processing, whereas responses to standards occurred primarily in alpha (8-12 Hz) range consistent with known frequencies of thalamocortical activation. Independent deficits in schizophrenia were observed in both the theta response to deviants (P=0.021) and the alpha-response to standards (P=0.003). At the single-trial level, differential patterns of response were observed for frequency vs duration/intensity deviants, along with At the network level, MMN deficits engaged canonical somatomotor, ventral attention and default networks, with a differential pattern of engagement across deviant types (P<0.0001). Findings indicate that deficits in thalamocortical, as well as corticocortical, connectivity contribute to auditory dysfunction in schizophrenia. In addition, differences in ERSP and rsfcMRI profiles across deviant types suggest potential differential engagement of underlying generator mechanisms.
BACKGROUND AND PURPOSE Bones are widely innervated, suggesting an important role for the sympathetic regulation of bone metabolism, although there are controversial studies. We investigated the ...effects of propranolol in a model of experimental periodontal disease.
EXPERIMENTAL APPROACH Rats were assigned as follows: animals without ligature; ligated animals receiving vehicle and ligated animals receiving 0.1, 5 or 20 mg·kg−1 propranolol. After 30 days, haemodynamic parameters were measured by cardiac catheterization. Gingival tissues were removed and assessed for IL‐1β, TNF‐α and cross‐linked carboxyterminal telopeptides of type I collagen (CTX) by elisa, or intercellular adhesion molecule 1 (ICAM‐1), receptor activator of NF‐κ B ligand (RANKL) and osteoprotegerin (OPG) by Western blot analysis. Sections from the mandibles were evaluated for bone resorption. Also, we analysed the ability of propranolol to inhibit osteoclastogenesis in vitro.
RESULTS Propranolol at 0.1 and 5 mg·kg−1 reduced the bone resorption as well as ICAM‐1 and RANKL expression. However, only 0.1 mg·kg−1 reduced IL‐1β, TNF‐α and CTX levels as well as increased the expression of OPG, but did not alter any of the haemodynamic parameters. Propranolol also suppressed in vitro osteoclast differentiation and resorptive activity by inhibiting the nuclear factor of activated T cells (NFATc)1 pathway and the expression of tartrate‐resistant acid phosphatase (TRAP), cathepsin K and MMP‐9.
CONCLUSIONS AND IMPLICATIONS Low doses of propranolol suppress bone resorption by inhibiting RANKL‐mediated osteoclastogenesis as well as inflammatory markers without affecting haemodynamic parameters.
The increasing integration of distributed renewable energy sources, such as photovoltaic (PV) systems, requires adequate regulatory schemes in order to reach economic sustainability. Incentives such ...as Feed-in Tariffs and Net Metering are seen as key policies to achieve this objective. While the Feed-in Tariff scheme has been widely applied in the past, it has now become less justified mainly due to the sharp decline of the PV system costs. Consequently, the Net Metering scheme is being adopted in several countries, such as Brazil, where it has is in force since 2012. In this context, this paper aims to estimate the minimum monthly residential demand for prosumers located in the different distribution concession areas in the interconnected Brazilian system that ensures the economic viability of the installation of PV systems. In addition, the potential penetration of PV-based distributed generation (DG) in residential buildings is also estimated. This study was conducted for the entire Brazilian interconnected system and it demonstrates that the integration of distributed PV systems is technical-economic feasible in several regions of the country reinforcing the role of the distributed solar energy in the diversification of Brazilian electricity matrix.
•We size PV systems for a demand range in all 63 Brazilian distribution agents.•We calculate the LCOE associated to each PV system for residential prosumers.•We calculate the threshold demand for the entire Brazilian interconnected system.•We consider all regulations and normative resolution in force in Brazil.•We estimate The PV potential penetration for residential buildings.
Objective
An association between bipolar disorder and cognitive impairment has repeatedly been described, even for euthymic patients. Findings are inconsistent both across primary studies and ...previous meta‐analyses. This study reanalysed 31 primary data sets as a single large sample (N = 2876) to provide a more definitive view.
Method
Individual patient and control data were obtained from original authors for 11 measures from four common neuropsychological tests: California or Rey Verbal Learning Task (VLT), Trail Making Test (TMT), Digit Span and/or Wisconsin Card Sorting Task.
Results
Impairments were found for all 11 test‐measures in the bipolar group after controlling for age, IQ and gender (Ps ≤ 0.001, E.S. = 0.26–0.63). Residual mood symptoms confound this result but cannot account for the effect sizes found. Impairments also seem unrelated to drug treatment. Some test‐measures were weakly correlated with illness severity measures suggesting that some impairments may track illness progression.
Conclusion
This reanalysis supports VLT, Digit Span and TMT as robust measures of cognitive impairments in bipolar disorder patients. The heterogeneity of some test results explains previous differences in meta‐analyses. Better controlling for confounds suggests deficits may be smaller than previously reported but should be tracked longitudinally across illness progression and treatment.
Objectives
We investigated functional trajectories after severe COVID-19 and estimated their associations with adverse outcomes (falls, rehospitalizations, institutionalization, or death), cognition ...and post COVID-19 condition within 1-year of hospital discharge.
Design
Prospective cohort study.
Setting
A large academic medical center in Sao Paulo, Brazil.
Participants
Survivors of COVID-19 admissions to an intensive care unit.
Interventions
None.
Measurements
We evaluated participants’ disability status before hospital admission and three, six, nine, and twelve months after discharge using 15 activities of daily living. During follow-up, cognition and post COVID-19 condition (defined as persistent symptoms with duration ≥2 months) were assessed. A latent class growth analysis was performed to investigate functional trajectories after discharge.
Results
We included 422 participants (median age 63 years, 13.5% were frail before COVID-19). Four distinct functional trajectories could be identified: “minimal disability trajectory” (37.4% of participants), “mild disability trajectory” (37.9%), “moderate disability trajectory” (16.8%), and “severe disability trajectory” (7.8%). Compared with minimal disability trajectory, the odds ratios (95% confidence interval) for 1-year adverse outcomes were 2.28 (1.38–3.76) for minor disability trajectory; 4.21 (2.10–8.42) for moderate disability trajectory; and 4.16 (1.51–11.46) for severe disability trajectory, even after adjustments. The occurrence of post COVID-19 condition was 67.5% and associated with functional trajectories (p=0.004). Cognition was also associated with functional trajectories.
Conclusion
Severe COVID-19 survivors can experience diverse functional trajectories, with those presenting higher levels of disability at increased risk for long-term adverse outcomes. Further investigations are essential to confirm our findings and assess the effectiveness of rehabilitation interventions, aiming to improve health outcomes in those who survived severe COVID-19 and other causes of sepsis.
Personalizing non-small-cell lung cancer (NSCLC) therapy toward oncogene addicted pathway inhibition is effective. Hence, the ability to determine a more comprehensive genotype for each case is ...becoming essential to optimal cancer care.
We developed a multiplexed PCR-based assay (SNaPshot) to simultaneously identify >50 mutations in several key NSCLC genes. SNaPshot and FISH for ALK translocations were integrated into routine practice as Clinical Laboratory Improvement Amendments-certified tests. Here, we present analyses of the first 589 patients referred for genotyping.
Pathologic prescreening identified 552 (95%) tumors with sufficient tissue for SNaPshot; 51% had ≥1 mutation identified, most commonly in KRAS (24%), EGFR (13%), PIK3CA (4%) and translocations involving ALK (5%). Unanticipated mutations were observed at lower frequencies in IDH and β-catenin. We observed several associations between genotypes and clinical characteristics, including increased PIK3CA mutations in squamous cell cancers. Genotyping distinguished multiple primary cancers from metastatic disease and steered 78 (22%) of the 353 patients with advanced disease toward a genotype-directed targeted therapy.
Broad genotyping can be efficiently incorporated into an NSCLC clinic and has great utility in influencing treatment decisions and directing patients toward relevant clinical trials. As more targeted therapies are developed, such multiplexed molecular testing will become a standard part of practice.
Under salt stress conditions, plant growth is reduced due to osmotic, nutritional and oxidative imbalance. However, salicylic acid acts in the mitigation of this abiotic stress by promoting an ...increase in growth, photosynthesis, nitrogen metabolism, synthesis of osmoregulators and antioxidant enzymes. In this context, the objective was to evaluate the effect of salicylic acid doses on the growth and physiological changes of eggplant seedlings under salt stress. The experiment was conducted in a greenhouse, where the treatments were distributed in randomized blocks using a central composite matrix Box with five levels of electrical conductivity of irrigation water (CEw) (0.50; 1.08; 2.50; 3.92 and 4.50 dS m-1), associated with five doses of salicylic acid (SA) (0.00; 0.22; 0.75; 1.28 and 1.50 mM), with four repetitions and each plot composed of three plants. At 40 days after sowing, plant height, stem diameter, number of leaves, leaf area, electrolyte leakage, relative water content, and total dry mass were determined. ECw and SA application influenced the growth and physiological changes of eggplant seedlings. Increasing the ECw reduced growth in the absence of SA. Membrane damage with the use of SA remained stable up to 3.9 dS m-1 of ECw. The relative water content independent of the CEw increased with 1.0 mM of SA. The use of SA at the concentration of 1.0 mM mitigated the deleterious effect of salinity on seedling growth up to 2.50 dS m-1 of ECw.
Rationale
Paired-associate learning (PAL), as part of the Cambridge Neuropsychological Test Automated Battery, is able to predict who from an at-risk population will develop Alzheimer’s disease. ...Schizophrenic patients are also impaired on this same task. An automated rodent model of PAL would be extremely beneficial in further research into Alzheimer’s disease and schizophrenia.
Objective
The objective of this study was to develop a PAL task using touchscreen-equipped operant boxes and test its sensitivity to manipulations of the hippocampus, a brain region of interest in both Alzheimer’s disease and schizophrenia.
Materials and methods
Previous work has shown that spatial and non-spatial memory can be tested in touchscreen-equipped operant boxes. Using this same apparatus, rats were trained on two variants of a PAL task differing only in the nature of the S− (the unrewarded stimuli, a combination of image and location upon the screen). Rats underwent cannulation of the dorsal hippocampus, and after recovery were tested under the influence of intra-hippocampally administered glutamatergic and cholinergic antagonists while performing the PAL task.
Results
Impairments were seen after the administration of glutamatergic antagonists, but not cholinergic antagonists, in one of the two versions of PAL.
Conclusions
De-activation of the hippocampus caused impairments in a PAL task. The selective nature of this effect (only one of the two tasks was impaired), suggests the effect is specific to cognition and cannot be attributed to gross impairments (changes in visual learning). The pattern of results suggests that rodent PAL may be suitable as a translational model of PAL in humans.
Fluoride is routinely used as a highly effective antibacterial agent that interferes with bacterial metabolism through fundamentally different mechanisms. One of the major bacterial evasion ...mechanisms against fluoride is the impermeability of cell envelope to the anion that limits its cellular uptake. Therefore, translating such compounds to clinical settings requires novel mechanisms to facilitate the uptake of membrane-impermeant molecules. Published data have indicated antibiotic synergy between fluoride and membrane destabilizing agents that induce strong fluoride toxicity in bacteria via enhancing the permeability of bacterial membranes to fluoride. Here, we report a similar mechanism of antibiotic synergy between fluoride and potassium ion carriers, valinomycin and monensin against Gram-positive bacteria, B. subtilis and S. aureus. Molecular dynamics simulations were performed to understand the effect of potassium on the binding affinity of fluoride to monensin and valinomycin. The trajectory results strongly indicated that the monensin molecules transport fluoride ions across the cell membrane via formation of ion-pair between the monensin-K
complex and a fluoride. This study provides new insights to design novel compounds to enhance the uptake of small toxic anions via synergistic interactions and thus exert strong antibacterial activity against a wide variety of pathogens.
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